chr1-153932256-C-T

Variant names:

• chr1-153932256-C-T
• rs774912358
• NM_014856.3:c.3944G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014856.3(DENND4B):​c.3944G>A​(p.Ser1315Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DENND4B NM_014856.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

Genes affected

DENND4B (HGNC:29044): (DENN domain containing 4B) Enables guanyl-nucleotide exchange factor activity. Involved in regulation of Rab protein signal transduction. Located in Golgi apparatus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000284738 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13803011).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND4B	NM_014856.3	c.3944G>A	p.Ser1315Asn	missense_variant	Exon 24 of 28	ENST00000361217.9	NP_055671.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND4B	ENST00000361217.9	c.3944G>A	p.Ser1315Asn	missense_variant	Exon 24 of 28	1	NM_014856.3	ENSP00000354597.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000241 AC: 6 AN: 248874 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461676 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3944G>A (p.S1315N) alteration is located in exon 24 (coding exon 23) of the DENND4B gene. This alteration results from a G to A substitution at nucleotide position 3944, causing the serine (S) at amino acid position 1315 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.69
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.097
Sift	Benign	0.094	T
Sift4G	Uncertain	0.021	D
Polyphen		0.0	B
Vest4		0.34
MutPred		0.52		Gain of relative solvent accessibility (P = 0.0023);
MVP		0.093
MPC		0.67
ClinPred		0.16	T
GERP RS		3.3
Varity_R		0.083
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs774912358; hg19: chr1-153904732;